Erythromycins A through D, represented by formula (E),
__________________________________________________________________________ Erythromycin R.sup.a R.sup.b __________________________________________________________________________ A B C D --OH --H --OH --H --CH.sub.3 --CH.sub.3 --H --H __________________________________________________________________________
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Morimoto et al. describes the preparation of 6-O-methyl erythromycin A in J. Antibiotics 37:187 (1984). Morimoto et al. further discloses 6-O-alkyl erythromycin A derivatives in J. Antibiotics, 43:286 (1990) and in European Patent Application 272,110, published Jun. 22, 1988. European Patent Application 215,355, published Mar. 28, 1987, discloses 6-O-loweralkyl erythromycins as stimulants of gastrointestinal contractile motion.
U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A derivatives in which the substituents are selected from alkyl, --CONH.sub.2, --CONHC(O)alkyl and --CONHSO.sub.2 alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives, and PCT application WO 97/17356, published May 15, 1997, discloses 3-deoxy-3-descladinose erythromycin derivatives. PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methyl erythromycin A derivatives. Certain intermediates to the present invention are disclosed in U.S. patent application Ser. No. 08/888,350.
European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxo erythromycin A derivatives.